The therapeutic use of pyrimidine nucleosides in the treatment of proliferative disorders has been well documented in the art. By way of example, commercially available antitumor agents of the pyrimidine series include 5-fluorouracil (Duschinsky, R., et al., J. Am. Chem. Soc., 79, 4559 (1957)), Tegafur (Hiller, S A., et al., Dokl. Akad. Nauk USSR, 176, 332 (1967)), UFT (Fujii, S., et al., Gann, 69, 763 (1978)), Carmofur (Hoshi, A., et al., Gann, 67, 725 (1976)), Doxyfluridine (Cook, A. F., et al., J. Med. Chem., 22, 1330 (1979)), Cytarabine (Evance, J. S., et al., Proc. Soc. Exp. Bio. Med., 106. 350 (1961)), Ancytabine (Hoshi, A., et al., Gann, 63, 353, (1972)) and Enocytabine (Aoshima, M., et al., Cancer Res., 36, 2726 (1976)).
EP 536936 (Sankyo Company Limited) discloses various 2′-cyano-2′-deoxy-derivatives of 1-β-D-arabinofuranosylcytosine which have been shown to exhibit valuable anti-tumour activity. One particular compound disclosed in EP 536936 is 2′-cyano-2′-deoxy-N4-palmitoyl-1-β-D-arabinofuranosylcytosine (referred to hereinafter as “682” or “CYC682”); this compound is currently under further investigation.
CYC682, also known as 1-(2-C-cyano-2-dioxy-(3-D-arabino-pentofuranosyl)-N4-palmitoyl cytosine, (Hanaoka, K., et al, Int. J. Cancer, 1999:82:226-236; Donehower R, et al, Proc Am Soc Clin Oncol, 2000: abstract 764; Burch, P A, et al, Proc Am Soc Clin Oncol, 2001: abstract 364), is an orally administered novel 2′-deoxycytidine antimetabolite prodrug of the nucleoside CNDAC, 1-(2-C-Cyano-2-deoxy-β-D-arabino-pentafuranosyl)-cytosine.

CYC682 has a unique mode of action over other nucleoside metabolites such as gemcitabine in that it has a spontaneous DNA strand breaking action, resulting in potent anti-tumour activity in a variety of cell lines, xenograft and metastatic cancer model.
CYC682 has been the focus of a number of studies in view of its oral bioavailability and its improved activity over gemcitabine (the leading marketed nucleoside analogue) and 5-FU (a widely-used antimetabolite drug) based on preclinical data in solid tumours. Recently, investigators reported that CYC682 exhibited strong anticancer activity in a model of colon cancer. In the same model, CYC682 was found to be superior to either gemcitabine or 5-FU in terms of increasing survival and also preventing the spread of colon cancer metastases to the liver (Wu M, et al, Cancer Research, 2003:63:2477-2482). To date, phase I data from patients with a variety of cancers suggest that CYC682 is well tolerated in humans, with myelosuppression as the dose limiting toxicity.
More recent studies have focussed on different crystalline forms of CYC682 (see for example, WO 02/064609 in the name of Sankyo Company Limited) and optimised formulations containing CYC682 which exhibit improved stability and which allow easier processing (see for example, WO 07/072,061 in the name of Cyclacel Limited).
The preparation of CYC682 described in EP 536936 (see Scheme 1 below) involves reacting cytidine [1] with palmitic anhydride in DMF to form N4-palmitoylcytidine [2] and subsequently protecting with 1,3-dichloro-1,1,4,4-tetraisopropyldisiloxane (CIPS) to form intermediate [3]. Oxidation of [3] with pyridinium dichromate/acetic anhydride in dichloromethane produces intermediate ketone [4], which is then reacted with sodium cyanide and sodium dihydrogen phosphate dihydrate in ethyl acetate to form the cyanohydrin [5]. Intermediate [5] is then reacted with N,N-dimethylaminopyridine, phenoxythiocarbonyl chloride and triethylamine to form intermediate [6], which is subsequently reacted with AIBN and tributyltin hydride in toluene to give intermediate [7]. Deprotection of [7] with acetic acid and tetrabutylammonium fluoride in THF yields the desired product, CYC682.

Further modifications to the above described route have been disclosed in JP 07053586 (Sankyo Company Limited). In particular, JP 07053586 discloses that the oxidation step can be achieved using 2,2,6,6-tetramethyl piperidinyloxy free radical (TEMPO), NaOCl and an alkali metal halide (see conversion of [3a] to [4a] in Scheme 2 below). Furthermore, conversion of ketone [4a] to cyanohydrin intermediate [5a] can be achieved by treating [4a] with acetone cyanohydrin instead of NaCN. The resulting cyanohydrin [5a] can then be treated with 2-naphthylchlorothioformate to give intermediate [6a].

However, in spite of these modifications, the above described routes are associated with relatively poor yields and/or a high level of variability, thereby highlighting the need for improved synthetic strategies.
The present invention thus seeks to provide an improved process for preparing CYC682. More specifically, the invention seeks to provide a synthetic route which gives rise to improved yields of CYC682 and/or which is suitable for the large scale preparation of this compound.